The present invention is directed to a process for preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof.
3S-3-amino-3-aryl propionic acid derivatives of the formula I 
wherein
R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R2 is hydrogen, alkyl or aralkyl, or acid addition salts thereof, are useful as intermediates in the synthesis of compounds described in WO 97/41102, which is incorporated by reference herein. Compounds described in WO 97/41102 are antagonists of the platelet fibrinogen receptor (gp IIb/IIIa antagonist) and thus are useful for treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina and vaso-occlusive disorders.
Known methods for preparing compounds of Formula I include an asymmetric Michael addition of lithium N-(trimethylsilyl)-(R)-phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl xcex2-aminoester [Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org. Chem. 1993, 58, 7948]. This process results in inefficient formation of lithium amide and difficult removal of N-xcex1-methylbenzyl group.
J. Org. Chem. vol. 61, p. 2222 (1996) discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomerically pure sulfinimine, the product of which is purified by chromatography and deprotected under acidic conditions to afford the xcex2-amino ester in greater than 90% ee. The need for chromatography makes this process unattractive for large-scale production. Similarly, J. Org. Chem., vol 64, p. 12 (1999) discloses a process wherein a titanium enolate of methyl acetate is added to an enantiomerically pure t-butylsulfinimine to afford the xcex2-amino ester in about 90% ee.
WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t-butylbromoacetate to the enantiomerically pure imine prepared from 3-pyridine carboxaldehyde and (R)-2-phenylglycinol. Oxidative cleavage of the N-(1-phenyl-2-hydroxy ethyl) group with NaIO4 in ethanol followed by acid hydrolysis affords the enantiomerically pure t-butyl xcex2-amino ester. Use of oxidizing agents makes this process unattractive for large-scale production.
WO 97/41102 discloses enzymatic resolution of the (xc2x1)xcex2-phenylacetamido acid using penicillin amidase to afford the S-acid. This process, which utilizes enzymes, is inefficient and impractical for large scale production.
Thus there exists a need for a process which is compatible with large scale production needs and which achieves acceptable levels of purity and yield.
The invention is directed to a process of making a compound of formula I, as described above, comprising reacting a compound of formula II, 
wherein R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl, at a pH range of between about 7 and about 11, to form a compound of formula III 
wherein R5 is N-t-butoxycarbonyl,
reacting a compound of formula III with at least 0.5 equivalents of (1R,2S)-(xe2x88x92)ephedrine, in an alkyl acetate solvent, to form a salt of formula IV 
wherein Ph is phenyl, reacting the salt of formula IV with an inorganic base in water to form a carboxylate salt of the compound of formula V, acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5, to form the compound of formula V 
xe2x80x83reacting the compound of formula V, at a temperature less than about 25xc2x0 C., to form the compound of formula I.
In another aspect, the invention is directed to a novel crystal form of (3S)-3-[(tert-butoxy)carbonyl]amino-3-[3xe2x80x2-pyridyl]propionic acid, the intermediate of formula Va 
wherein Boc is (tert-butoxy)carbonyl designated Form 2 and characterized by its x-ray powder diffraction patterns.
As used herein, unless otherwise noted, xe2x80x9calkylxe2x80x9d whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 10 carbon atoms. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like.
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, xe2x80x9carylxe2x80x9d shall refer to unsubstituted aromatic groups such as phenyl, napthyl, and the like. The aryl group may be substituted with one or two substituents. Suitable substituents on the aryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, xe2x80x94NR32, wherein R3 is alkyl; and R4CONH, wherein R4 is phenyl or alkyl.
As used herein, unless otherwise noted, xe2x80x9cheteroarylxe2x80x9d shall denote any five or six membered monocyclic ring structure containing at least one heteroatom selected from O, N and S or a bicyclic ring system wherein the heteroaryl is fused to an aryl group. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, isoquinolyl, quinolyl, isothiazolyl, and the like. The heteroaryl may be substituted with one or two substituents. Suitable substituents on the heteroaryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, xe2x80x94NR32, wherein R3 is alkyl; and R4CONH, wherein R4 is phenyl or alkyl. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure, except when the heteroaryl contains only one heteroatom, then the heteroaryl must be attached at a carbon atom.
Preferably, the heteroaryl is pyridyl. The preferred heteroaryl may be substituted with one or two substituents as described above. Most preferably, the pyridyl is unsubstituted.
As used herein, unless otherwise noted, xe2x80x9caralkylxe2x80x9d shall mean any alkyl group substituted with an aryl group such as phenyl, napthyl and the like.
As used herein, unless otherwise noted, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, xe2x80x9can acid of pKa less than or equal to threexe2x80x9d includes monochloroacetic, dichloroacetic, trichloroacetic, hydrochloric, hydrobromic, hydroiodic, perchloric, picric, nitric, sulfuric, phosphoric, methanesulfonic, tosic, trifluoromethanesulfonic, trifluoracetic, potassium bisulfate, sodium bisulfate, citric and the like.
As used herein, unless otherwise noted, xe2x80x9cinorganic basexe2x80x9d shall mean a base having a monovalent cation component, such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetrabutyl ammonium hydroxide, trimethylbenzyl ammonium hydroxide and the like.
As used herein, unless otherwise noted, xe2x80x9calkyl alcoholxe2x80x9d shall denote a hydroxy derivative of the above described straight or branched chain alkyl groups. For example, methanol, ethanol, N-propanol, isopropanol, isobutanol, t-butanol and the like.
As used herein, the notation xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d shall denote the presence of a stereogenic center having the S or R configuration.
In a preferred embodiment of the invention, in the compound of formula I, R1 is unsubstituted phenyl, substituted phenyl, unsubstituted pyrimidyl, substituted pyrimidyl, unsubstituted pyridyl, substituted pyridyl, unsubstituted napthyl or substituted naphthyl. Suitable substituents are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, xe2x80x94NR32, wherein R3 is alkyl, and R4CONH, wherein R4 is phenyl or alkyl. More preferably, R1 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methylpyridyl, 5-bromopyridyl, 6-chloropyridyl or 5,6-dichloropyridyl. Most preferably R1 is 3-pyridyl. Preferably R2 is alkyl, more preferably methyl or ethyl, most preferably methyl.
In an embodiment of the present invention, wherein the compound of formula I is present as an acid addition salt, the acid is an acid of pKa less than or equal to three, as defined above, other than potassium bisulfate, sodium bisulfate and citric acid. Preferably the compound of formula I is a hydrochloric acid addition salt.
The present invention is directed to a process of making a compound of formula I 
wherein R1 and R2 are as described above, or acid addition salt thereof, which comprises reacting a compound of formula II 
to form a compound of formula III 
wherein R5 is N-t-butoxycarbonyl, reacting a compound of formula III to form a salt of formula IV 
wherein Ph is phenyl, reacting the salt of formula IV to form the compound of formula V 
reacting the compound of formula V to form the compound of formula I.
In accordance with the invention, a compound of formula II, a known compound or compound prepared by known methods [Profft, V. E.; Becker, F. J., J. Prakt. Chem. 1965, 30(1-2), 18] is reacted with di-tert-butyl dicarbonate in an organic solvent such as 1,4-dioxane, tert-butanol or tetrahydrofuran, preferably tetrahydrofuran, with addition of an aqueous solution of an inorganic base, as previously defined, preferably sodium hydroxide, at a temperature in the range of about 0xc2x0 to about 100xc2x0 C., preferably at a temperature between about 0xc2x0 and about 35xc2x0 C., at a pH in the range of about 7 to about 11, preferably at a pH of between about 9.9 and about 10.2, to form the compound of formula III.
Preferably, the desired compound of formula III is isolated by removal of the organic solvent by evaporation under reduced pressure, followed by acidification of the remaining aqueous solution by addition of an acid of pKa of less than or equal to three, as defined above, preferably sodium bisulfate or citric acid, to a pH of between about 3.5 and about 6.5, preferably to a pH of about 3.8, filtration or extraction with an organic solvent, such as methylene chloride, 1,2-dichloroethane, chloroform, dioxane, toluene, alkyl acetate such as ethyl acetate or mixtures thereof, preferably ethyl acetate, and optionally removal of the organic solvent by evaporation under reduced pressure.
The compound of formula III is reacted with at least 0.5 equivalents of (1R,2S)-(xe2x88x92)ephedrine, preferably 0.5 to 1.0 equivalent of (1R,2S)-(xe2x88x92)ephedrine, in an alkyl acetate solvent, preferably ethyl acetate, at a temperature from about 25xc2x0 to about 78xc2x0 C., to form the salt of formula IV.
The salt of formula IV is reacted with an inorganic base, as previously defined, preferably, sodium hydroxide, in water to form a carboxylate salt of the compound of formula V (dissolved in the aqueous solution).
The desired compound of formula V is isolated by removal of the (1R,2S)-(xe2x88x92)ephedrine by extraction with an organic solvent which is largely immiscible with water such as methylene chloride, 1,2-dichloroethane, alkyl acetate or aromatic hydrocarbon, such as toluene, or ketone, such as methyl-isobutyl ketone, followed by acidification of the remaining aqueous solution by addition of an acid of pKa less than or equal to three, as defined above, preferably sodium bisulfate or sulfuric, to a pH of between about 3.5 and about 6.5, preferably to a pH of about 3.8, and filtration to afford the compound of formula V. When the organic solvent which is largely immiscible with water is toluene, preferably the aqueous solution containing the compound of formula V is heated to a temperature in the range of about 70-80xc2x0 C. prior to extraction with the toluene and cooled to about room temperature after extraction with the toluene and prior to acidification.
The compound of formula V is reacted with an acid of pKa less than or equal to three, as defined above, other than potassium bisulfate, sodium bisulfate and citric acid, preferably hydrochloric acid, in a C1-C10 alkyl alcohol, preferably methanol, at a temperature less than about 25xc2x0 C., to form the corresponding compound of formula I, which is isolated by conventional methods, such as filtration.
Form 2 of the compound of formula Va may be characterized by its x-ray powder diffraction pattern utilizing a Siemens D5000 diffractometer and the following system conditions:
a) CuKxcex1 radiation, 35 mA, 40 KV
b) Optics
1 mm slit, Goebel mirrors, 0.6 mm slit, and vertical soller slits between tube and sample
LiF monochromator between sample and detector
c) Scan 5 to 35xc2x02xcex8 at 0.02 Step Size at rate of 1xc2x02xcex8/minute
d) Zero background sample holder
The following examples describe the invention in greater detail and are intended to illustrate the invention, but not to limit it.